{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:49:01Z","timestamp":1777092541901,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lateral Project of Lunan Pharmaceutical Group Co., Ltd","award":["JT120924080306"],"award-info":[{"award-number":["JT120924080306"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>With increasing environmental pollution and a high incidence of respiratory infections, pulmonary nodules (PN) are being detected more frequently. Although most are benign, they are often accompanied by chronic inflammation and localized fibrosis, which may predispose patients to progression toward idiopathic pulmonary fibrosis (IPF). However, the biological relationship between benign pulmonary nodules (BPNs) and IPF remains poorly understood. Therefore, this study aims to investigate the shared molecular mechanisms and identify potential biomarkers linking BPN and IPF, with the goal of elucidating the pathogenic transition from BPN to IPF. In this study, microarray data from GEO datasets were systematically analyzed to explore shared molecular mechanisms, immune infiltration characteristics, and potential early intervention strategies linking BPN and IPF. Differential expression analysis, protein\u2013protein interaction (PPI) networks, weighted gene co-expression network analysis (WGCNA), and integrative machine learning approaches identified MME and ANKRD23 as key hub genes associated with the transition from BPN to IPF. Both genes demonstrated strong diagnostic performance, with Area Under the Curve (AUC) values exceeding 0.7, and were significantly correlated with immune cell infiltration, particularly effector memory CD8+ T cells. Functional enrichment and gene set enrichment analyses indicated that these genes were mainly involved in immune-related processes in BPN, while in IPF, ANKRD23 was linked to cytoskeletal organization and genomic stability, and MME was enriched in profibrotic pathways such as TGF-\u03b2 signaling. The diagnostic value of these biomarkers was further validated in a bleomycin-induced IPF mouse model using quantitative polymerase chain reaction (qPCR). In addition, drug\u2013gene interaction prediction and molecular docking analyses highlighted several naturally derived compounds with favorable binding affinity and anti-inflammatory properties, among which folic acid, curcumin, and arbutin emerged as promising candidates for safe early intervention. Collectively, these findings identify MME and ANKRD23 as potential biomarkers for early identification of BPN patients at risk of developing IPF and provide a theoretical basis for early diagnosis and targeted preventive strategies.<\/jats:p>","DOI":"10.3390\/ijms27083647","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"3647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Local Tissue Repair to Fibrosis: Deciphering Gene Co-Expression Networks in Benign Pulmonary Nodules and Idiopathic Pulmonary Fibrosis Comorbidity via Bioinformatics and Machine Learning"],"prefix":"10.3390","volume":"27","author":[{"given":"Yaoyu","family":"Xie","sequence":"first","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingzhe","family":"Gao","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Ren","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoran","family":"Sun","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siju","family":"Lou","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangli","family":"Yan","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0399-5085","authenticated-orcid":false,"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Sun","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"National Lung Screening Trial Research Team, Aberle, D.R., Adams, A.M., Berg, C.D., Black, W.C., Clapp, J.D., Fagerstrom, R.M., Gareen, I.F., Gatsonis, C., and Marcus, P.M. (2011). Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N. Engl. J. Med., 365, 395\u2013409.","DOI":"10.1056\/NEJMoa1102873"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa1911793","article-title":"Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial","volume":"382","author":"Scholten","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1148\/radiol.2462070712","article-title":"Fleischner Society: Glossary of Terms for Thoracic Imaging","volume":"246","author":"Hansell","year":"2008","journal-title":"Radiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e93S","DOI":"10.1378\/chest.12-2351","article-title":"Evaluation of Individuals with Pulmonary Nodules: When Is It Lung Cancer?","volume":"143","author":"Gould","year":"2013","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.diii.2013.05.007","article-title":"Management Strategy of Pulmonary Nodule in 2013","volume":"94","author":"Lederlin","year":"2013","journal-title":"Diagn. Interv. Imaging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1164\/rccm.201308-1483ST","article-title":"An Official American Thoracic Society\/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias","volume":"188","author":"Travis","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12967-023-04798-w","article-title":"Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans","volume":"22","author":"Liu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(11)60052-4","article-title":"Idiopathic Pulmonary Fibrosis","volume":"378","author":"King","year":"2011","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1056\/NEJMra2005230","article-title":"Spectrum of Fibrotic Lung Diseases","volume":"383","author":"Wijsenbeek","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.1164\/rccm.201807-1255ST","article-title":"Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS\/ERS\/JRS\/ALAT Clinical Practice Guideline","volume":"198","author":"Raghu","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMra1705751","article-title":"Idiopathic Pulmonary Fibrosis","volume":"378","author":"Lederer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2300752","DOI":"10.1183\/13993003.00752-2023","article-title":"Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis","volume":"63","author":"Wijsenbeek","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1016\/S0140-6736(11)60405-4","article-title":"Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (CAPACITY): Two Randomised Trials","volume":"377","author":"Noble","year":"2011","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1183\/09031936.00107206","article-title":"Pulmonary Hypertension in Patients with Pulmonary Fibrosis Awaiting Lung Transplant","volume":"30","author":"Shorr","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1183\/09031936.00077309","article-title":"Idiopathic Pulmonary Fibrosis: A Disease with Similarities and Links to Cancer Biology","volume":"35","author":"Vancheri","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1084\/jem.20110551","article-title":"Integrating Mechanisms of Pulmonary Fibrosis","volume":"208","author":"Wynn","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e01065","DOI":"10.1002\/rcr2.1065","article-title":"Pulmonary Sarcoidosis with a Cavitary Lesion in the Lung Caused by a TNF-\u03b1 Inhibitor: A Case Report","volume":"10","author":"Hamada","year":"2022","journal-title":"Respirology Case Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107798","DOI":"10.1016\/j.pharmthera.2020.107798","article-title":"Idiopathic Pulmonary Fibrosis: Disease Mechanisms and Drug Development","volume":"222","author":"Spagnolo","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","article-title":"Shared and Distinct Mechanisms of Fibrosis","volume":"15","author":"Distler","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1586\/ers.10.73","article-title":"Viral Infection and Aging as Cofactors for the Development of Pulmonary Fibrosis","volume":"4","author":"Naik","year":"2010","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1164\/rccm.201010-1752OC","article-title":"Viral Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis","volume":"183","author":"Wootton","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110070","DOI":"10.1016\/j.intimp.2023.110070","article-title":"TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization","volume":"118","author":"Luo","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.redox.2015.06.019","article-title":"Redox Regulation of FoxO Transcription Factors","volume":"6","author":"Klotz","year":"2015","journal-title":"Redox Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, J., Zhai, X., Sun, X., Cao, S., Yuan, Q., and Wang, J. (2022). Metabolic Reprogramming of Pulmonary Fibrosis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1031890"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1089\/ars.2007.1908","article-title":"Extracellular Superoxide Dismutase in Pulmonary Fibrosis","volume":"10","author":"Gao","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Leithner, K., Wohlkoenig, C., Stacher, E., Lindenmann, J., Hofmann, N.A., Gall\u00e9, B., Guelly, C., Quehenberger, F., Stiegler, P., and Smolle-J\u00fcttner, F.-M. (2014). Hypoxia Increases Membrane Metallo-Endopeptidase Expression in a Novel Lung Cancer Ex Vivo Model\u2013Role of Tumor Stroma Cells. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-40"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.molmet.2019.01.006","article-title":"Membrane Metallo-Endopeptidase (Neprilysin) Regulates Inflammatory Response and Insulin Signaling in White Preadipocytes","volume":"22","author":"Ramirez","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1165\/rcmb.4791","article-title":"Acute Cigarette Smoke\u2013Induced Connective Tissue Breakdown Requires Both Neutrophils and Macrophage Metalloelastase in Mice","volume":"27","author":"Churg","year":"2002","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s11658-024-00647-w","article-title":"Research Progress of Ankyrin Repeat Domain 1 Protein: An Updated Review","volume":"29","author":"Xu","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: The Human Gene Integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ling, S.S.M., Chen, Y.T., Wang, J., Richards, A.M., and Liew, O.W. (2017). Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071362"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1002","DOI":"10.1038\/cddis.2013.525","article-title":"Ankrd2 Is a Modulator of NF-\u03baB-Mediated Inflammatory Responses during Muscle Differentiation","volume":"5","author":"Bean","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1002\/cam4.4606","article-title":"Associations of Systemic Inflammation Markers with Identification of Pulmonary Nodule and Incident Lung Cancer in Chinese Population","volume":"11","author":"Tian","year":"2022","journal-title":"Cancer Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.anai.2016.09.427","article-title":"Effect of Curcumin on Nasal Symptoms and Airflow in Patients with Perennial Allergic Rhinitis","volume":"117","author":"Wu","year":"2016","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.biocel.2008.06.010","article-title":"Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases","volume":"41","author":"Aggarwal","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_36","first-page":"261","article-title":"Anti-Inflammatory and Antiallergic Activity of Arbutin against Ovalbumin-Induced Allergic Rhinitis in Mice through the Modulation of Inflammatory Responses","volume":"18","author":"Zhang","year":"2022","journal-title":"Pharmacogn. Mag."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Asbaghi, O., Ashtary-Larky, D., Bagheri, R., Moosavian, S.P., Nazarian, B., Afrisham, R., Kelishadi, M.R., Wong, A., Dutheil, F., and Suzuki, K. (2021). Effects of Folic Acid Supplementation on Inflammatory Markers: A Grade-Assessed Systematic Review and Dose\u2013Response Meta-Analysis of Randomized Controlled Trials. Nutrients, 13.","DOI":"10.3390\/nu13072327"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/1074-5521(95)90120-5","article-title":"Mitomycin C: Small, Fast and Deadly (But Very Selective)","volume":"2","author":"Tomasz","year":"1995","journal-title":"Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s12935-022-02624-9","article-title":"Anticancer Potential of Alkaloids: A Key Emphasis to Colchicine, Vinblastine, Vincristine, Vindesine, Vinorelbine and Vincamine","volume":"22","author":"Dhyani","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting Batch Effects in Microarray Expression Data Using Empirical Bayes Methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/bioinformatics\/btv313","article-title":"DSigDB: Drug Signatures Database for Gene Set Analysis","volume":"31","author":"Yoo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A Comprehensive Gene Set Enrichment Analysis Web Server 2016 Update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:24:49Z","timestamp":1777091089000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,19]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083647"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083647","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,19]]}}}